Interferon-inducible cell-intrinsic host defense against Chlamydia trachomatis

干扰素诱导的细胞内在宿主针对沙眼衣原体的防御

• 批准号: 10559601
• 负责人: Joern Coers
• 金额: $ 45.78万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10559601
• 关键词: Adaptive Immune System; Anti-Bacterial Agents; Bacterial Infections; Binding Proteins; Cell Culture System; Cells; Chemicals; Chlamydia; Chlamydia Infections; Chlamydia muridarum; Chlamydia trachomatis; Development; Disease; Dynamin; Ectopic Pregnancy; Epidemic; Epithelial Cells; Failure; Family; Female infertility; Functional disorder; Genes; Genetic Screening; Genomics; Goals; Growth; Guanosine Triphosphate Phosphohydrolases; Helper-Inducer T-Lymphocyte; Host Defense; Host resistance; Human; Immune; Immune response; Immune system; Immunity; Immunologic Stimulation; Infection; Infertility; Inflammasome; Inflammation; Inflammatory; Interferon Type II; Interferons; Knowledge; Libraries; Life; Link; Lymphocyte; Mediating; Modeling; Monitor; Mus; Mutagens; Mutate; Mutation; Natural Immunity; Neutrophil Activation; Neutrophil Infiltration; Organoids; Pathogenesis; Pathway interactions; Pelvic Inflammatory Disease; Phenotype; Predisposition; Prophylactic treatment; Proteins; Regulation; Research; Resistance; Rodent; Role; Sexually Transmitted Diseases; Signal Transduction; T-Lymphocyte; Therapeutic; Therapeutic Intervention; United States; Vaccine Design; Vaccines; Vacuole; Virulence Factors; Woman; Work; adaptive immunity; bacterial genetics; chronic infection; cytokine; design; endometrial organoid; functional genomics; gain of function; gene function; guanylate; immunopathology; improved; in vivo; insight; interdisciplinary approach; loss of function; member; mouse model; mutant; mycobacterial; nonsynonymous mutation; novel; novel therapeutics; overexpression; pathogen; pathogenic bacteria; programs; prophylactic; receptor; recruit; resistance factors; response; sensor; therapy design; vaccine strategy

Chlamydia trachomatis is the cause for the most common bacterial sexually transmitted infection in the United States. Commonly referred to as a silent epidemic, C. trachomatis infections in women are frequently asymptomatic, and often go unnoticed and untreated. The infection can persist for months or years and ultimately cause pelvic inflammatory disease, ectopic pregnancies, and infertility. In order to establish persistent infections, C. trachomatis must subvert both the innate and the adaptive branches of the immune system. A central node that connects adaptive and innate immunity to C. trachomatis is the cytokine gamma-interferon (IFNγ). This cytokine is produced by lymphocytes such as T cells of the adaptive immune system and induces cell-intrinsic, innate host defenses against Chlamydia in epithelial cells. In order to overcome IFNγ-mediated immunity and replicate inside human epithelial cells, C. trachomatis evolved counterdefenses specifically adapted to its human host. These C. trachomatis counterdefenses and the corresponding repertoire of IFNγ-inducible anti-Chlamydia defense programs are poorly characterized. Our goal is to decipher this interplay between IFNγ-mediated host defense and chlamydial counterdefense, as such knowledge holds the potential to instruct the design of improved treatment options. To achieve this goal under Aim1, we designed unbiased functional genomics screens to identify human IFNγ-inducible genes (ISGs) that exert potent anti-Chlamydia defenses. In parallel we employ defined C. trachomatis mutant libraries in functional bacterial genetic screens to identify C. trachomatis genes that subvert ISG- driven defense pathways. As proof-of-principle we already identified i) human ISGs with not-previously- described anti-Chlamydia activities and ii) C. trachomatis mutants that are hyper-susceptible to IFNγ- activated host defenses in human cells. These novel human defense pathways and the corresponding C. trachomatis evasion mechanisms will be characterized through multidisciplinary approaches in Aim1. As an interrelated second aim, we will dissect the role of IFNγ in C. trachomatis-induced inflammation, which underlies Chlamydia-associated diseases. Although best known as a potent inducer of cell-intrinsic immunity, IFNγ also functions as a critical regulator of inflammation and associated diseases. We discovered that specific members of the superfamily of IFNγ-inducible dynamin-like GTPases control Chlamydia-induced activation of inflammasomes, a class of cytosolic immune sensors that drive inflammation. Using organoid and other mouse and human cell culture systems as well as novel in vivo mouse models, we will in Aim2 define the function of IFNγ-inducible GTPases in Chlamydia-triggered inflammation and in vivo pathogenesis. These studies will reveal critical insights into the role of IFNγ in the immunopathology of Chlamydia infections with the potential to guide the development of new therapeutic or prophylactic treatments or vaccine designs.

沙眼衣原体是最常见的细菌性传播感染的原因， 美国的通常被称为沉默的流行病，C。妇女的沙眼感染经常是 无症状，往往不被注意和治疗。感染可以持续数月或数年， 最终导致盆腔炎、宫外孕和不孕。为了建立 持续感染、C.沙眼必须破坏免疫系统的先天和适应性分支， 系统一个连接适应性免疫和先天性免疫与C.沙眼是细胞因子 γ-干扰素（IFNγ）。这种细胞因子由淋巴细胞如适应性免疫系统的T细胞产生。 系统，并诱导细胞内在的，先天性宿主防御上皮细胞中的衣原体。为了 克服IFNγ介导的免疫并在人上皮细胞内复制，C.沙眼演化 专门适应人类宿主的防御系统这些C.沙眼的反防御和 IFNγ诱导的抗衣原体防御程序的相应库的特征很差。我们 我们的目标是破译IFNγ介导的宿主防御和衣原体防御之间的相互作用， 这些知识具有指导设计改进的治疗方案的潜力。实现这一 在Aim 1的目标下，我们设计了无偏倚的功能基因组学筛选，以鉴定人IFNγ诱导的 基因（ISG）发挥有效的抗衣原体防御。同时，我们使用定义的C。沙眼衣原体 功能性细菌遗传筛选中的突变体库以识别C.沙眼病毒基因，破坏ISG- 驱动防御路径。作为原理证明，我们已经鉴定了i）人类ISG与先前未- 描述了抗衣原体活性和ii）C.对IFNγ高度敏感的沙眼突变体， 激活人体细胞中的宿主防御这些新的人类防御途径和相应的 C.沙眼逃避机制将通过多学科方法的特点，在目标1。作为 作为相互关联的第二个目标，我们将剖析IFNγ在C.沙眼引起的炎症， 导致衣原体相关疾病虽然最有名的是作为一种有效的诱导细胞内 IFNγ还作为炎症和相关疾病的关键调节剂发挥作用。我们 发现IFNγ诱导的动力蛋白样GTP酶超家族的特定成员控制 衣原体诱导的炎性小体激活，这是一类细胞溶质免疫传感器， 炎症使用类器官和其他小鼠和人类细胞培养系统以及新的体内 在小鼠模型中，我们将在Aim 2中定义IFNγ诱导的GTP酶在衣原体触发的 炎症和体内发病机制。这些研究将揭示IFNγ在肿瘤发生中的重要作用。 衣原体感染的免疫病理学，有可能指导新的治疗或 预防性治疗或疫苗设计。